Abstract 3402: In vivo efficacy of RAF/MEK clamp avutometinib (VS-6766) in combination with FAK inhibition in low grade serous ovarian cancer
Authors: Blair McNamara, Cem Demirkiran, Stefania Bellone, Levent Mutlu, Margherita Zipponi, Miguel S. Verzosa, Justin Harold, Tobias M. Hartwich, Gary Altwerger, Elena Ratner, Gloria Huang, Mitchell Clark, Vaagn Andikyan, Masoud Azodi, Peter E. Schwartz, Peter Dottino, Alessandro D. Santin
Journal: Cancer Research (2023)

Abstract Objective: Low grade serous carcinoma (LGSC) of the ovary is characterized by a high recurrence rate, resistance to most chemotherapeutic agents, and limited effective therapeutic options. Recently, LGSC has been found to often contain mutations in KRAS (~30%), NRAS (~10%), and BRAF (~8%). Avutometinib (VS-6766) is a RAF/MEK clamp that induces dominant negative complexes of RAF with MEK, and inhibits proliferation of KRAS, NRAS, BRAF, and CRAF mutant cell lines. VS-4718 is a focal adhesion kinase (FAK) inhibitor that has shown synergistic anti-tumor activity with avutometinib in other cancer models, as it blocks the potential of FAK to function as an adaptive resistance mechanism to RAF/MEK inhibition. This study aimed to determine the efficacy of the RAF/MEK clamp avutometinib with FAK inhibition in vivo in LGSC patient derived tumor xenograft (PDX) models. Methods: Whole-exome sequencing was used to evaluate mutations in two primary ovarian LGSC PDX models (OVA(K)250 and PERIT(M)17). OVA(K)250 and PERIT(M)17 cells were injected into SCID mice and animals were treated with either vehicle control (CTRL), RAF/MEK clamp avutometinib (MEKi), FAK inhibitor VS-4718, or the combination (MEKi/FAKi). Tumor volumes were measured twice per week. Results: Both the OVA(K)250 and PERIT(M)17 PDX models express wildtype KRAS and express RAF1 mutations at position 12641679 A&amp;gt;C, V207G. In PDX OVA(K)250 mice treated with MEKi/FAKi, day 9 tumor volume was significantly lower compared to mice treated with CTRL (p=0.0002). At day 9, tumor volume was also significantly lower in mice treated with MEKi alone compared to CTRL (p=0.0007). Mice treated with FAKi alone had tumor volumes that were significantly smaller than CTRL by day 12 (p=0.009). By day 23, CTRL mice had reached tumor volume characteristics requiring sacrifice. Combination MEKi/FAKi treatment resulted in improved overall survival (OS); median OS for combination or MEKi alone was not reached by 60 days. Treatment with FAKi led to median OS of 35 days; CTRL mice had median OS of 23 days (p=0.001). In vivo experiments with PDX PERIT(M)17 and PDX OVA(K)250 are ongoing. Conclusion: Combination of avutometinib with FAK inhibition showed improved in vivo preclinical anti-tumor efficacy relative to either agent alone in an LGSC PDX model with wildtype KRAS and with a RAF1 mutation. These data support an ongoing registration-directed study with avutometinib ± the FAK inhibitor defactinib for patients with recurrent LGSC (NCT04625270). Citation Format: Blair McNamara, Cem Demirkiran, Stefania Bellone, Levent Mutlu, Margherita Zipponi, Miguel S. Verzosa, Justin Harold, Tobias M. Hartwich, Gary Altwerger, Elena Ratner, Gloria Huang, Mitchell Clark, Vaagn Andikyan, Masoud Azodi, Peter E. Schwartz, Peter Dottino, Alessandro D. Santin. In vivo efficacy of RAF/MEK clamp avutometinib (VS-6766) in combination with FAK inhibition in low grade serous ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3402.